Risk Factors for Non-Adherence to Medication for Liver Transplant Patients: An Umbrella Review.

Background/Objectives: Liver Transplantation (LT) is the second most common solid organ transplantation. Medication adherence on LT patients is key to avoiding graft failure, mortality, and important quality of life losses. The aim of this study is to identify risk-factors for non-adherence to treatment of liver transplant patients according to reliable published evidence. Methods: An umbrella review within the context of adherence to immunosuppressant medication of LT patients, was conducted. The review was performed in accordance with the principles of the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines. Results: A total of 11 articles were finally included for the review. Non-adherence factors were identified and allocated using the WHO classification of factors for non-adherence. Each of these groups contains a subset of factors that have been shown to influence adherence to medication, directly or indirectly, according to literature findings. Conclusions: The results of the review indicate that sociodemographic factors, factors related to the patient, factors related to the treatment, condition-related and health system-related factors are good categories of predictors for both adherence and non-adherence to immunosuppressive medication in LT patients. This list of factors may help physicians in the treating and recognizing of patients with a potential risk of non-adherence and it could help in the designing of new tools to better understand non-adherence after LT and targeted interventions to promote adherence of LT patients.

Neuropsychological rehabilitation in patients with relapsing-remitting multiple sclerosis: a systematic review.

Introduction: Multiple sclerosis (MS) is an autoimmune, chronic, inflammatory and demyelinating disease that affects the Central Nervous System (CNS). It is the most common disabling neurological disease in young patients not caused by traumatic shock. Depending on how symptoms appear and how often they occur, there are different subtypes of MS. One of them is the relapsing-remitting phenotype (R-R), which the symptoms appear in the form of isolated outbreaks which, little by little, are causing the increase of the disease and its sequelae. MS encompasses a wide variety of symptoms, including possible cognitive impairment. In the literature there is no clear methodology and a defined and structured consensus to carry out neuropsychological rehabilitation processes in this group.Aim: This study aims to review and synthesize the available scientific evidence about the neuropsychological intervention on cognitive impairment of people with multiple sclerosis, relapsing-remitting subtype.Methods: Keywords for database search (Pubmed and Wos) were established, as well as inclusion and exclusion criteria. Then, the articles were selected according to inclusion and exclusion criteria; methodological quality criteria were applied. Articles published in the last 10 years were included.Results: Fifteen articles that met the established criteria were selected. Most of these studies identify as effective their cognitive rehabilitation programs, some of them showed changes in neural structures after rehabilitation.Discussion: It seems that cognitive rehabilitation is effective in influencing cognitive deterioration in R-R MS. This highlights the importance of neuropsychological evaluation and intervention from the early stages of the disease.

Factors Associated with Therapeutic Adherence in Multiple Sclerosis in Spain.

Purpose: Adherence to disease-modifying therapies (DMTs) in multiple sclerosis (MS) is a complex and multidimensional phenomenon. Identifying the predictors of therapeutic adherence in MS will guide the design of interventions to improve health outcomes. Our aim was to assess the degree of adherence to pharmacological treatments, assess the relationship between patient-related factors and pharmacological adherence and to identify predictors of adherence to pharmacological treatments in patients with MS in Spain. Patients and Methods: A cross-sectional nationwide study was carried out in Spain between December 2020 and September 2021. The web-based evaluation protocol consisted of a self-questionnaire survey designed ad hoc and the application of validated questionnaires to assess adherence, as well as beliefs about medication and quality of life. Predictor variables of adherence to MS treatment were assessed using multivariate analysis. Results: A total of 152 patients with MS participated (mean age: 44 years; 64% were female; and 78% had relapsing-remitting MS). Seventy-three percent of the patients reported being adherent to their pharmacological treatment for MS. Forgetfulness was the most common cause of non-adherence. Necessity beliefs and concerns beliefs were not statistically associated with adherence. The adherent group shows statistically significant better levels of quality of life in the cognitive function subscale than the non-adherent participants (p=0.040). Role limitations-emotional, emotional well-being and overall quality of life were not significantly associated with adherence. Predictors with a statistical association with adherence to treatment were years of education (OR=0.79; 95% CI: 0.65-0.96; p=0.020) and intravenous treatment (OR=3.17; 95% CI: 1.07-9.45; p=0.038). Conclusion: We found an adequate adherence to pharmacological treatment. Low education and intravenous treatment were significant predictors of adherence to DMTs.

Multicentre study of magnet ingestion in Spanish paediatric emergency departments.

INTRODUCTION: The ingestion of magnetic objects can cause complications in children, and there are no epidemiological or clinical data on the subject in Spain. OBJECTIVES: To determine the incidence, epidemiological characteristics and management of magnet ingestion in paediatric emergency departments in Spain. MATERIAL AND METHODS: Prospective observational multicentre study conducted over a 3-year period. The study universe consisted of patients aged less than 14 years. RESULTS: The incidence was 4.8 cases per 100 000 emergency care episodes. Of the 72 patients included (mean age, 7.2 years), 54% were male. Seven percent had neuropsychiatric disorders. Sixty-one percent of the magnets were spherical and 69% came from toys. The size was variable, most frequently between 5 and 10 mm (50%), and ranging from 3 to 30 mm. Eighty-six percent of patients were asymptomatic. The most frequent symptom was abdominal pain. Eighty-three percent of the patients sought medical care within 6 h of ingestion and 92% within 24 h. Thirty-one percent of the cases were of multiple ingestion. Endoscopy was required for extraction in 15% of cases, a proportion that rose to 36% in the group of cases of multiple ingestion. None of the patients required surgery. We did not observe any gastrointestinal complications of magnet ingestion. CONCLUSIONS: The ingestion of multiple magnets is less frequent than single magnet ingestion, and we did not observe any complications despite the lower frequency of procedures compared to other studies.

C. elegans expressing D76N ß2-microglobulin: a model for in vivo screening of drug candidates targeting amyloidosis.

The availability of a genetic model organism with which to study key molecular events underlying amyloidogenesis is crucial for elucidating the mechanism of the disease and the exploration of new therapeutic avenues. The natural human variant of ß2-microglobulin (D76N ß2-m) is associated with a fatal familial form of systemic amyloidosis. Hitherto, no animal model has been available for studying in vivo the pathogenicity of this protein. We have established a transgenic C. elegans line, expressing the human D76N ß2-m variant. Using the INVertebrate Automated Phenotyping Platform (INVAPP) and the algorithm Paragon, we were able to detect growth and motility impairment in D76N ß2-m expressing worms. We also demonstrated the specificity of the ß2-m variant in determining the pathological phenotype by rescuing the wild type phenotype when ß2-m expression was inhibited by RNA interference (RNAi). Using this model, we have confirmed the efficacy of doxycycline, an inhibitor of the aggregation of amyloidogenic proteins, in rescuing the phenotype. In future, this C. elegans model, in conjunction with the INVAPP/Paragon system, offers the prospect of high-throughput chemical screening in the search for new drug candidates.

Multidisciplinary Consensus on the Nonadherence to Clinical Management of Inhaled Therapy in Spanish asthma patients.

PURPOSE: Rates of nonadherence to asthma treatment in Spain are between 24% and 76%, which results in poor disease control and increased health care costs. The main objective of this multidisciplinary consensus was to investigate the opinions of health professionals and patients regarding adherence to inhaled therapy in Spain. The results will help to identify the causes of nonadherence and to establish strategies to detect and correct the problem. METHODS: This research was conducted by using a modified Delphi method organized into 2 rounds and involving a panel of 64 physicians, 16 nurses, and 10 community pharmacists. In addition, 70 patients with asthma completed a simplified 1-round survey, based on the Delphi questionnaire. The items proposed to reach a consensus included topics such as impact and causes of nonadherence, as well as strategies to improve adherence to treatment. FINDINGS: Expert panelists reached a consensus on ~80% of the items proposed. They agreed that the lack of control in asthma has an important economic impact. The causes of nonadherence with more agreement were the patients' beliefs about treatment and the complexity of the inhalation devices. Panelists agreed that the most important strategies to improve adherence were modification of patients' beliefs, training of professionals in the management of adherence, and personalization of interventions. Most patients only agreed with items that referred to strategies to improve adherence. IMPLICATIONS: Although the problems, impact, causes, and interventions regarding nonadherence to asthma treatment are known, adequate monitoring of adherence to treatment is not performed. A multidisciplinary and personalized approach is necessary to control and improve adherence.

[Cord blood procalcitonin in the assessment of early-onset neonatal sepsis]. / Procalcitonina en sangre de cordón en la valoración del riesgo de sepsis neonatal precoz.

INTRODUCTION: Early diagnosis of early-onset neonatal sepsis (EONS) is essential to reduce morbidity and mortality. Procalcitonin (PCT) in cord blood could provide a diagnosis of infected patients from birth. OBJECTIVE: To study the usefulness and safety of a procedure for the evaluation of newborns at risk of EONS, based on the determination of PCT in cord blood. PATIENTS AND METHODS: Neonates with infectious risk factors, born in our hospital from October 2013 to January 2015 were included. They were processed according to an algorithm based on the values of cord blood procalcitonin (< 0.6ng/ml versus ≥0.6ng/ml). They were later classified as proved infection, probable, or no infection. RESULTS AND CONCLUSIONS: Of the 2,519 infants born in the study period, 136 met inclusion criteria. None of 120 cases with PCT<0.6ng/ml in cord blood developed EONS (100% negative predictive value). On the other hand, of the 16 cases with PCT ≥0.6ng/ml, 10 were proven or probably infected (62.5% positive predictive value). The sensitivity of the PCT against infection was 100%, with a specificity of 95.2% (area under the receiver operator curve 0.969). The incidence of infection in the study group was 7.4%, and 26.1% in cases with maternal chorioamnionitis. 21 newborn (15.4%) received antibiotic therapy. The studied protocol has shown to be effective and safe to differentiate between patients with increased risk of developing an EONS, in those where the diagnostic and therapeutic approach was more interventionist, versus those with less likelihood of sepsis, who would benefit from a more conservative management.

Enhanced toxicity of silver nanoparticles in transgenic Caenorhabditis elegans expressing amyloidogenic proteins.

The increasing number of applications of silver nanoparticles (AgNP) prompted us to assess their toxicity in vivo. We have investigated their effects on wild type and transgenic Caenorhabditis elegans (C. elegans) strains expressing two prototypic amyloidogenic proteins: ß2-microglobulin and Aß peptide3-42. The use of C. elegans allowed us to highlight AgNP toxicity in the early phase of the worm's life cycle (LC50 survival, 0.9 µg/ml). A comparative analysis of LC50 values revealed that our nematode strains were more sensitive to assess AgNP toxicity than the cell lines, classically used in toxicity tests. Movement and superoxide production in the adult population were significantly affected by exposure to AgNP; the transgenic strains were more affected than the wild type worms. Our screening approach could be applied to other types of nanomaterials that can enter the body and express any nanostructure-related bioactivities. We propose that C. elegans reproducing the molecular events associated with protein misfolding diseases, e.g. Alzheimer's disease and systemic amyloidosis, may help to investigate the specific toxicity of a range of potentially harmful molecules. Our study suggests that transgenic C. elegans may be used to predict the effect of chemicals in a "fragile population", where an underlying pathologic state may amplify their toxicity.

C. elegans expressing human ß2-microglobulin: a novel model for studying the relationship between the molecular assembly and the toxic phenotype.

Availability of living organisms to mimic key step of amyloidogenesis of human protein has become an indispensable tool for our translation approach aiming at filling the deep gap existing between the biophysical and biochemical data obtained in vitro and the pathological features observed in patients. Human ß(2)-microglobulin (ß(2)-m) causes systemic amyloidosis in haemodialysed patients. The structure, misfolding propensity, kinetics of fibrillogenesis and cytotoxicity of this protein, in vitro, have been studied more extensively than for any other globular protein. However, no suitable animal model for ß(2)-m amyloidosis has been so far reported. We have now established and characterized three new transgenic C. elegans strains expressing wild type human ß(2)-m and two highly amyloidogenic isoforms: P32G variant and the truncated form ΔN6 lacking of the 6 N-terminal residues. The expression of human ß(2)-m affects the larval growth of C. elegans and the severity of the damage correlates with the intrinsic propensity to self-aggregate that has been reported in previous in vitro studies. We have no evidence of the formation of amyloid deposits in the body-wall muscles of worms. However, we discovered a strict correlation between the pathological phenotype and the presence of oligomeric species recognized by the A11 antibody. The strains expressing human ß(2)-m exhibit a locomotory defect quantified with the body bends assay. Here we show that tetracyclines can correct this abnormality confirming that these compounds are able to protect a living organism from the proteotoxicity of human ß(2)-m.

The two tryptophans of ß2-microglobulin have distinct roles in function and folding and might represent two independent responses to evolutionary pressure.

BACKGROUND: We have recently discovered that the two tryptophans of human ß2-microglobulin have distinctive roles within the structure and function of the protein. Deeply buried in the core, Trp95 is essential for folding stability, whereas Trp60, which is solvent-exposed, plays a crucial role in promoting the binding of ß2-microglobulin to the heavy chain of the class I major histocompatibility complex (MHCI). We have previously shown that the thermodynamic disadvantage of having Trp60 exposed on the surface is counter-balanced by the perfect fit between it and a cavity within the MHCI heavy chain that contributes significantly to the functional stabilization of the MHCI. Therefore, based on the peculiar differences of the two tryptophans, we have analysed the evolution of ß2-microglobulin with respect to these residues. RESULTS: Having defined the ß2-microglobulin protein family, we performed multiple sequence alignments and analysed the residue conservation in homologous proteins to generate a phylogenetic tree. Our results indicate that Trp60 is highly conserved, whereas some species have a Leu in position 95; the replacement of Trp95 with Leu destabilizes ß2-microglobulin by 1 kcal/mol and accelerates the kinetics of unfolding. Both thermodynamic and kinetic data fit with the crystallographic structure of the Trp95Leu variant, which shows how the hydrophobic cavity of the wild-type protein is completely occupied by Trp95, but is only half filled by Leu95. CONCLUSIONS: We have established that the functional Trp60 has been present within the sequence of ß2-microglobulin since the evolutionary appearance of proteins responsible for acquired immunity, whereas the structural Trp95 was selected and stabilized, most likely, for its capacity to fully occupy an internal cavity of the protein thereby creating a better stabilization of its folded state.